The various benefits of using a variety of phosphate esters, as their salts, in oral care formulations have been reported for decades. U.S. Pat. No. 4,152,421 refers to the use of alkali metal or alkanolamine salts of alkyl phosphate esters in dentifrice formulations, citing the high foaming property of the high monoalkyl content phosphate esters (monoalkyl:dialkyl phosphate, or MAP:DAP, weight ratio of 70:30-100:0) as novel, in combination with the “known” property of having no substantial after effects on the tastes and flavors of foods and drinks, especially citrus juices. The concept and range of structures is expanded in a subsequent patent, U.S. Pat. No. 5,370,865, which emphasizes the pleasant taste of basic amino acid salts, specifically with lysine, arginine and histidine. Another early patent, U.S. Pat. No. 4,264,580, covers the incorporation of 0.2-1.0% of an anionic phosphate ester mixture (monoalkyl:dialkyl weight ratios of 1:10 to 10:1) in order to simply reduce the grain formation in a sodium lauryl sulfate-calcium carbonate composition to produce a smooth paste. The next useful property claimed in U.S. Pat. No. 4,350,680 is reduction in the sloughing or desquamation of oral mucosa during tooth brushing action if at least 0.2% of an anionic phosphate ester surface active agent is used as an additional surfactant to sodium lauryl sulfate. U.S. Pat. No. 5,019,373 attempted to improve upon these patents by claiming special advantages for the incorporation of shorter alkyl chain (C6 to C9) dialkyl phosphate esters, particularly dioctyl phosphate. The phosphate ester concentration was rather high, at 2-4 wt. %, in the dentifrice formulation. Evidence for anti-caries activity was offered, which showed a lower rate of calcium demineralization on teeth (in vitro) treated with 1% dioctyl phosphate solution compared to both a 1% sodium lauryl sulfate, which was similar to plain water (placebo), and 1 ppm sodium fluoride (the positive control).
The important subject of remineralization was extensively discussed in a series of patents by Winston and Usen, U.S. Pat. Nos. 5,603,922; 5,605,675; and 5,628,429. Saliva is naturally saturated with calcium and phosphate ions and promotes slow, natural remineralization of carious lesions. The use of supersaturated calcium phosphate solutions or slurries to enhance this natural process was ineffective for a variety of reasons. An effective technique was reported to be the sequential application of concentrated solutions of soluble calcium and phosphate salts to the tooth as disclosed in U.S. Pat. Nos. 4,083,955 and 4,397,837. However, this method was inconvenient and time consuming. In particular, one problem with these techniques is that the remineralization process may stop before the lesion is completely and uniformly remineralized, or “repaired”. The rapid remineralization results in a build up of remineralized material on the tooth surface, which then prevents diffusion of the ions into the deeper regions of the lesion, resulting in a void or structure weakening fault in the calcium hydroxyapatite mineral crystal lattice. Furthermore, the solution offered by Winston and Usen was to ultimately develop a two-part toothpaste with water soluble calcium salts in one part and inorganic phosphate salts in the other, along with a two chambered toothpaste tube to deliver it. Prolonged contact of the two salts would result in premature precipitation of the insoluble calcium phosphate salts, which then would not redissolve, hence would be inert as far as the remineralization process is concerned. When the two parts were combined on the tooth brush and promptly introduced into the oral cavity, however, the supersaturated calcium phosphate solution would form in situ and bathe the tooth surface during the brushing process, providing brief periods of replenishment of the ions to enhance the natural process.
More recently, the emphasis has been on the property of the phosphate ester to bond strongly to tooth enamel and dentin and carry other organic components with it. J. Olsson et al. studied the ability of phosphate esters and alkyl ethoxylates to deposit onto hydroxyapatite (HA) in the presence of saliva and inhibit the adherence of Streptococcus mutans to the surface. (See Caries Res. 1991, (25), 51, J. Olsson, A. Carlen and K. Holmberg.) By 14C labeling experiments, it was determined that 0.20-0.35 mg of the dodecyl—3 EO monoalkyl phosphate (Rhodia counterpart, DERMALCARE® MAP-L-230) bonded to 40 mg HA compared to <0.05 mg of the hexadecyl—8 EO ethoxylate. It was postulated that the phosphate formed a bi-layer, as evidenced by the increased negative charge of the surface. Addition of the ester and ethoxylate together resulted in a decrease in the ester uptake and an increase in the ethoxylate uptake, suggesting that, instead of the second phosphate ester layer, an ethoxylate layer formed on the phosphate layer bound to the HA. An essentially zero surface charge supported this. The phosphate esters alone reduced the deposition of the S. mutans but the most dramatic results were obtained when they were used together with the ethoxylate. Olsson's conclusion, namely “ . . . the fact that the concomitant incubation of HA, saliva, agents [the ester and ethoxylate], and bacteria seems to increase the effectiveness of the treatment even more than was obtained after pretreatments followed by washings indicates that additional [beneficial] effects may result from exposing the bacteria and salivary components to the surfactants. Indeed, this is . . . particularly relevant if, e.g. treatment is to be performed as a mouth rinsing procedure”, is important to commercial applications of phosphate esters in oral care products.
Shortly following this study, Japanese Application No. JP 05-320032 disclosed that dentifrices (mouthwash) containing monoalkyl enriched phosphate ester salt mixtures (e.g. MAP:DAP 90:10 w/w), calcium scavengers (e.g. sodium tripolyphosphate), phenol derivatives and, optionally, water soluble fluorides, formed a film on the surface of the teeth to prevent dental plaque formation and improve acid resistance.
In later filed applications, U.S. Pat. No. 5,605,676 (hereinafter '676 patent) and U.S. Pat. No. 6,110,445 (hereinafter '445 patent), it was disclosed that the uptake and retention of antibacterial agents on dental tissue is substantially increased by incorporation of a phosphate ester surfactant into the formulation. The '676 patent showed that the uptake was inhibited, in a dose response manner, by addition of sodium lauryl sulfate and in the '445 patent disclosed that the anti-bacterial effect is enhanced by use of sodium lauryl sulfate in combination with monolauryl phosphate. The preferred phosphate ester was identified as MAP-20H, manufactured by Kao Corporation (Rhodia counterpart, DERMALCARE® MAP-L-200). Rapid and continued disinfectant action against oral bacteria was also taught for oral care products containing anti-bacterial quaternary ammonium salts of phosphate esters, optionally in combination with the arginine salts, for a pleasant taste in U.S. Pat. No. 5,374,418. It should also be noted that oral care compositions containing phosphate esters and cationic antibacterial agents had been reported decades earlier in GB Patent No. 1,475,251.
Several references citing phosphate ester derivatives were found which were specifically concerned with reduction of hypersensitivity, the subject of this application. The most informative of these was U.S. Pat. No. 5,891,233 (hereinafter '233 patent). The '233 patent discloses a method for reducing pulpal irritation by treating the tooth surface, cavity, or root canal with a bioactive silica containing glass, which releases silica to the surface in a concentration effective to induce crystallization of apatite in the dental tubules and/or on the tooth surface. The '233 patent discloses that a high concentration of calcium and phosphate ions should be maintained in the vicinity of the tubules long enough to allow the ions to diffuse into the tubules as deeply as possible. These concentrations alone, however, are not sufficient. The inventors state “one of the basic features relating to mineralization is that, although serum and tissue fluids [saliva] are supersaturated solutions with regard to calcium and phosphate, spontaneous crystallization does not take place . . . .” As disclosed, to cross the threshold from ion clusters to formation of a crystal nucleus (seed crystal) requires special conditions and/or an outside factor (nucleator). “At least at the beginning of the mineralization process, small membrane lining structures (matrix vesicles) can be seen on the surfaces of the cells forming hard tissue. The vesicles contain calcium binding lipids and alkaline phosphatase.” “Since these vesicles only appear at the beginning of the hard tissue formation, it is apparent that there must also be other mechanisms which lead to the mineralization of a tissue. In fact, the extra-cellular matrix contains quite a few organic molecules which may act as nucleators . . . . These molecules include, for example, osteonectin, phosphoproteins, collagen, anionic phospholipids and sulphur containing compounds such as chondroitin sulfate and ceratan sulfate.”
U.S. Pat. No. 6,416,745 also emphasizes blocking or plugging up the tubules as the best way to effectively correct hypersensitivity. The patent expands upon the concept by using liposomes (tiny balloons whose walls are lipid bi-layers) to deposit in the tubules and induce mineral [apatite] formation by acting as a mineral template that attracts soluble mineral ions that are naturally present in the dentin tubular fluid and saliva. “These liposome-surface-attracted soluble mineral ions precipitate from the dentin tubule fluid onto the liposome surface, which in turn, acts to nucleate mineral growth in the fluid. The mineral formed in the dentinal tubules will provide a massive, insoluble plug, thereby restoring the tubules to their healthy, naturally impermeable state, blocking tubule fluid movement and insulating the dentinal nerves.” Not all liposomes are effective; their surface must be anionic, preferably neutralized as sodium or potassium salts. Liposomes with a choline [amphoteric, e.g. lecithin] or inositol [nonionic, e.g. sugar] surface are not mineral-inducing. Liposomes derived from salts of di(oleoyl)phosphatidic acid (DOPA) are preferred (and the only example given). (Valuable information on liposomes and the sodium salt of DOPA is available on the supplier's web site, www.avantilipids.com.). Numerous other formulation ingredients are suggested such as abrasives, sudsing agents, flavoring agents, humectants, sweeteners, anti-bacterial agents, dyes, etc. Among the sudsing (surfactant) agents, such as sodium lauryl sulfate, alkyl phosphate esters are notably absent. Use of the liposomes in combination with other nerve desensitizing agents such as potassium nitrate, and anti-caries agents such as sodium fluoride, is emphasized in the claims. The experimental examples are minimal, however, and no clinical testing is provided to back up the claims.
Another approach, the use of a colloidal form of a polyvalent metal salt, such as zinc or aluminum (among many di- tri- and tetravalent metals claimed) of a polyol (sugar) phosphate ester to plug the tubules was reported in U.S. Pat. No. 5,244,651. Japanese patent, JP 10-298044, discloses the use of insoluble calcium alkyl phosphate salts to similarly plug the dentinal tubules as an effective way to treat hypersensitivity (hyperesthesia). This is, again, only a symptomatic treatment of the problem, not a resolution, as these plugs would inevitably wash out and not be as effective as the present invention.
Additionally, ways to effectively protect teeth from cavities and a variety of other problems by forming a protective, polymeric coating on them were investigated over thirty years ago. Up to that time, no polymeric coating had been found that could be effectively applied to the teeth, in the oral environment, which had the required adhesion, toughness and durability to survive, long term, in the warm, moist oral conditions in the presence of enzymes and under the harsh action of mastication. The use of “temporary” coatings often caused problems of their own. The coating would crack or lift up at its edges, allowing fluids containing bacteria, especially the Streptococcus mutans, to penetrate into these narrow fissures, where they could then flourish in a relatively protected area where tooth brush bristles could not dislodge them. Furthermore, it is known that it is not good oral hygiene practice to cut off the tooth surfaces from the active action of the saliva because it contains enzymes, minerals and other beneficial ingredients, calcium and phosphate ions, for instance, which promote slow, natural remineralization of the enamel and dentin surfaces at points of damage, within reason. (The caries develop because the acids released in the metabolism of sucrose by the S. mutans destroyed (that is, dissolved) the calcium hydroxyapatite structure more rapidly than this remineralization process could repair it.) It is also believed that the attachment of “unnatural” polymers to tooth structure is not a good idea because it disrupts the calcium hydroxyapatite crystal structure, potentially weakening it. Fluoride treatment, in contrast, was known to be beneficial because the tiny fluoride ion could be incorporated into the hydroxyapatite without seriously disrupting it and actually making it harder and more resistant to acid dissolution (decay). If in excess, however, it may contribute to undesirable discoloration of the tooth surface.
Temporary coatings might be helpful as an effective tooth protective system, however, if they could be conveniently applied by the individual (not requiring a visit to the dental office) and would penetrate effectively into the areas between the teeth, below the gum line and into the fissures (for instance in the top surfaces of molars). They should last from about a half-day to a week and leave no residue behind that would build up or disrupt the natural hydroxyapatite mineral structure. Accordingly, there is a need in the art for improved oral care formulations.